1675-P: Adipocyte Adaptive Immune Cell Function and Exhaustion Contribute to the Drop in Adipose Tissue (AT) Regulatory T-Cells (Tregs) in Human Obesity

Background: AT Tregs are decreased in obese mice. We have previously shown that preventing this decline improves insulin sensitivity, despite persistent obesity, underscoring a key role for AT Tregs in systemic metabolism. Therefore, we sought to examine AT Treg changes in human subjects and elucidate potential mechanisms responsible for these changes.

Methods: We obtained visceral (VAT) and subcutaneous adipose tissue (SAT) at elective surgery in 54 obese and 18 lean subjects, and SAT via liposuction in 15 lean subjects before and after 2 weeks high fat diet (HFD).

Results: Obese individuals had 67% less Treg abundance in VAT (p<0.001) and 79% in SAT (p<0.001); Tregs as %CD4+ cells correlated with insulin sensitivity and inversely with BMI. Subjects ingesting a HFD experienced a 50% drop in SAT Tregs (p<0.001), which correlated with decreased insulin sensitivity by clamp. To understand this drop, we next performed gene expression analyses on isolated adipocytes, AT T cells, and VAT Tregs. Obese adipocytes had profound increases in major histocompatibility class II (MHCII) genes, but decreases in fatty acid oxidation and mitochondrial genes, suggesting a functional switch from a primary metabolic to an adaptive immune cell. These changes were associated with decreased AT Treg abundance, and increased insulin resistance and BMI. T cells revealed increased Tbet, a proinflammatory CD4+ Th1 cell marker, and decreased FOXP3, a Treg marker, consistent with our demonstration that human adipocytes can present antigen to activate CD4+ Th1 cells. Obese vs. lean VAT Tregs also had a 3-fold (p<0.05) increase in the T cell exhaustion marker, program cell death protein-1 (PD-1), and a 75% (p<0.05) decrease in CD127, which is attenuated in exhausted T cells.

Discussion: Thus, human adipocyte immune cell activity, combined with Treg exhaustion, contributes to the drop in AT Tregs and strongly affects metabolism.